Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV clearance or resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis. We recently published work utilizing the chimpanzee experimental model that established for the first time the fundamental importance of the CD4+ T helper cell in HCV infection resolution: in chimpanzees that had previously resolved infection with HCV, experimental depletion of the CD4+ T cell compartment prior to re-infection with HCV resulted in the emergence of viral escape mutations, the inability to eliminate viremia and the establishment of chronic HCV infection. Accordingly, we now postulate that in the natural course of HCV infection, viral persistence is a direct result of the inadequacy of the CD4+ T cell compartment. Specifically, we hypothesize that the interaction between CD4+ T cells and professional antigen presenting cells (APCs) is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence. The work proposed here is based both on our work in the chimpanzee model and on observations in human patients. The experimental focus of this proposal is on defining the mechanisms by which T cells fail in persistent HCV infection. [unreadable] [unreadable] [unreadable]